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Show SCHOOL OF MEDICINE AND HEALTH SCIENCES UNDERGRADUATE RESEARCH ABSTRACTS PROTEIN PHOSPHATASE 2A ACTIVATION IS REQUIRED FOR LIPID-INDUCED ARTERIAL DYSFUNCTION IN MICE Xin Wan (David J. Symons) College of Health, and Division of Endocrinology, Metabolism, and Diabetes University of Utah We hypothesized that protein phosphatase 2A (PP2A) activation is required for lipid-induced, ce-ramide- mediated arterial dysfunction. Mice haploinsufficient for dihydroceramide desaturase (des1+/- ) and their wild-type littermates (desl +/+) were infused (iv) for 6 h with lard-oil (LO) or vehicle (veh). Subgroups of LO and veh mice were treated (1.5 mg/kg IP) for 3 days prior to infusion with the PP2A inhibitor LB1 (Lixte Biotechnology, NY). LO increased ceramide accrual in arteries from des1+/+ but not des1+/- mice. Palmitate (3h x 500 uM) increased (p<0.05) PP2A activity, and impaired (p<0.05) insulin-stimulated p-eNOS(S) 1177 to eNOS in endothelial cells, and these responses were negated by LB1 (4 uM; n=5-8). Endothelium-dependent and -independent relaxation of femoral arteries (~ 150 urn i.d.) was assessed using acetylcholine (ACh) and sodium nitroprusside (SNP), respectively (n=3 mice/group, 3 vessels/ mouse). ACh-mediated (2x108, 3x108, and 6x108 M) relaxation (%) was less (p<0.05) in LO desl +/+ (30±2,41 ±3, and 61 ±4, respectively) vs. veh desl +/+ mice (48±4, 67±6, and 73±6, respectively). Endothelial dysfunction observed in LO desl +/+ mice was less severe when ceramide accrual (i.e. LO desl +/- mice) or PP2A activation (i.e., LB1 + LO desl +/+ mice) were prevented. SNP-evoked vasorelaxation was intact among groups. LO-induced ceramide accumulation induces endothelial dysfunction that is dependent upon PP2A activation. John David Symons |
